PROJECT SUMMARY ? PROJECT 3 Most cases of cervical cancer occur among unscreened and under screened women. Strategies to increase screening among these women, including HPV self-testing, have therefore been identified as the most important cervical cancer screening research priority. HPV self-testing involves women using a device to collect their own cervicovaginal sample for HPV testing. International studies have repeatedly shown that many unscreened and under screened women will use an HPV self-test at home and return it by mail, and recent efforts in the United States (US), including our own work, have established the feasibility of implementing such mail-based programs. An important next step in this field of research is to examine the effectiveness and implementation of a large, mail-based HPV self-testing program in the US. The overall goal of the proposed project is to determine the effectiveness and implementation of a multi-level cervical cancer screening intervention that features HPV self-testing for unscreened and under screened women from Appalachia, a region with longstanding cervical cancer disparities. The intervention will include mail-based HPV self-testing (patient-level), healthcare provider education sessions about HPV self-testing (provider-level), and patient navigation for women who do not initially return their HPV self-test or who subsequently test positive for a high-risk (i.e., oncogenic) HPV infection (system-level). The proposed study will include 1180 unscreened and under screened Appalachian women who are ages 30-64 and be implemented as part of the integrated health system-based cervical cancer prevention program ?Improving Uptake of Cervical Cancer Prevention Services in Appalachia.? Importantly, the proposed project will take an effectiveness-implementation hybrid approach that will allow for the assessment of both intervention effectiveness and implementation. Specific aims will address each outcome type (service, implementation, and client outcomes) recommended for implementation research: Aim 1 (service outcomes) will determine the effectiveness of the multi-level intervention in increasing cervical cancer screening (primary outcome); Aim 2 (implementation outcomes) will assess the acceptability, fidelity, sustainability, and cost-effectiveness of the intervention; and Aim 3 (client outcomes) will determine satisfaction with the intervention at the patient-, provider-, and system-level. Each aim will make a significant research contribution and, taken together, will be one of the most innovative and comprehensive HPV self-testing efforts to date in the US. As HPV self-testing continues to emerge as a cervical cancer screening strategy in the US, these findings will provide an evidence base on both intervention effectiveness and implementation that will be highly valuable in guiding future HPV self-testing programs and cervical cancer screening policies.